K₂CO₃/18-Crown-6-Catalyzed Selective H/D Exchange of Heteroarenes with Bromide as a Removable Directing Group

Abstract

The K 2 CO 3 /18-crown-6-catalyzed H/D exchange of heretoarenes in high atom % deuterium incorporation is disclosed. The use of a weak base as a catalyst leads to excellent site selectivity and broad functional group tolerance. Control experiments indicated that the use of bromide, which enhances the adjacent C−H bond reactivity, as a removable directing group is essential. Moreover, conversion of bromide to other functional groups is also performed to construct other useful deuterated compounds.

Direct C–H Hydroxylation of N-Heteroarenes and Benzenes via Base-Catalyzed Halogen Transfer

“…We began by conducting deuterium exchange experiments to ascertain the most favorable site of deprotonation under the optimized conditions . These experiments were performed by mixing the (hetero)­arene substrate with deuterated methanol (CD 3 OD) and KO- t -Bu (Figure ).…”

H/D Exchange of Aromatic Sulfones via Base Promotion and Silver Catalysis

“…Base-facilitated HDX have been a long existing strategy for deuteration, where potent labeling systems have been developed continuously in recent years, including KO t Bu/DMSO- d 6 , K 2 CO 3 /18-crown-6, and NaTMP/PMDETA . In our previous work of pyridine deuteration, etoricoxib, a selective COX-2 inhibitor, was extensively deuterated by the KO t Bu/DMSO- d 6 system, in which the ortho-sites of the methylsulfonyl motif achieved an excellent labeling degree of 96% D. Encouraged by this promising result, the development of sulfone deuteration was commenced by this strong-base-promoted system, using (methylsulfonyl) benzene ( 1 ) as a model substrate.…”

Alkali-metal bases in catalytic hydrogen isotope exchange processes

“…Despite all these advances, the detailed study of the reaction mechanism is still lacking in some of these transformations. DFT calculations and key mechanistic experiments have been performed in a few examples, 13,16,18,21,23,27,28,30 but in general the specific mechanistic details of these processes are still poorly understood. We predict that further developments on the use of alkali-metal bases for HIE processes will keep appearing, which in combination with a deeper mechanistic understanding will bring the use of alkali-metal bases as an excellent pathway for the incorporation of deuterium and tritium into organic molecules, with the benefits of using widely available and cheap alkali-metal reagents.…”

“…7). 23 Remarkably the hydrogen isotope exchange is observed exclusively in the 4-position of the pyridine ring, in the ortho -position to the bromo group. The tolerance of a bromine allowed the further functionalization of the deuterated compounds via palladium catalysed cross-coupling, forming C–C bonds to access biaryls, alkynes, alkenes or esters.…”